Targeted molecular agents are a landmark achievement in cancer treatment. The tyrosine kinase inhibitor imatinib mesylate, known for its efficacy against the BCR-ABL fusion protein in chronic myelogenous leukemia, also targets the mutant KIT protein in gastrointestinal stromal tumor (GIST). However, while imatinib is remarkably effective against metastatic GIST, it almost never induces a complete response, and tumor progression occurs at a median of approximately 20 months, limiting patient survival. The objective of the curent project is to combine immunotherapy with imatinib to improve outcomes in GIST. In a transgenic mouse model of GIST, preliminary studies have shown that the anti-tumor effects of imatinib are partially immune-mediated, and that imatinib may have enhanced anti-tumor efficacy when combined with antibody-mediated blockade of CTLA-4, an immunomodulatory protein. In the current project, we will investigate the hypothesis and immunologic mechanisms by which CTLA-4 blockade enhances the anti-tumor effects of imatinib in both murine GIST and human tumor specimens. In Aim 1, we will determine the optimal dosing of combined imatinib and anti-CTLA-4 therapy for maximal tumor shrinkage in a mouse model of GIST. In Aim 2, we will determine if CTLA-4 blockade increases the antigen-specific CD8 T cell response against GIST in mice. In Aim 3, we will characterize how anti-CTLA-4 alters the imatinib-induced regulatory T cell (T Reg) response to the tumor in murine GIST. In Aim 4, we wil determine whether human intratumoral CD8 T cells are functional against GIST. We anticipate that our findings will advance our understanding of GIST and may establish the rationale for a novel clinical trial combining molecular and immunotherapy in GIST. We expect that our work will not only improve the lives of patients with these tumors, but also be relevant to other cancers in which targeted molecular therapy is used.